scholarly journals Qingre Huoxue Decoction, A Traditional Chinese Herbal Formulation, Impacts Angiogenesis in Psoriasis-Like Skin Through the HIF-1α/Flt-1/VEGF Pathway

2021 ◽  
Author(s):  
Wen Li ◽  
Xiang He ◽  
Jiong Zhu ◽  
Huimin Zhang
Keyword(s):  
Mouse Model ◽  
Cultured Cells ◽  
Capillary Tube ◽  
Severity Index ◽  
Tube Formation ◽  
Viability Assessment ◽  
Vegf Signaling ◽  
Herbal Formulation ◽  
Vegf Pathway

Abstract Background: Qingre Huoxue Decoction (QHD), a traditional Chinese medicine (TCM) formulation, could alleviate psoriasis in our previous studies. The present work aimed to assess QHD’s effects on psoriasis and the underpinning mechanism in cultured cells and experimental animals.Methods: The CCK-8 assay was carried out for cell viability assessment. HUVEC migration was assessed by transwell and wound healing assays. QHD-induced suppression of capillary tube formation in HUVECs was detected by tube formation assay. In addition, the imiquimod (IMQ)-induced male BALB/c mouse model of psoriasis was established to examine the Psoriasis Area and Severity Index (PASI) after QHD administration. HIF-1α, Flt-1 and VEGF expression levels in vivo were assessed by immunoblot, qPCR and immunofluorescence. Results: The results showed that QHD dose-dependently reduced viability in HUVECs. In addition, QHD suppressed tube formation in HUVECs at levels below those needed to inhibit HUVECs. Upon QHD administration, HUVEC migration was markedly decreased; QHD effectively prevented the migratory ability of HUVECs, as determined by wound areas at 0h, 12h and 24h, respectively. Finally, QHD starkly downregulated HIF-1α, Flt-1 and VEGF in the IMQ-induced mouse model, at the protein and mRNA levels.Conclusions: In summary, QHD inhibits angiogenesis in cultured cells and mice. HIF-1α/Flt-1/VEGF signaling is important in angiogenesis and psoriasis development. These findings provide a rationale for developing QHD for clinical use against psoriasis.

scholarly journals Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 252
Author(s):  
Jang Mi Han ◽  
Ye Seul Choi ◽  
Dipesh Dhakal ◽  
Jae Kyung Sohng ◽  
Hye Jin Jung
Keyword(s):  
Capillary Tube ◽  
Umbilical Vein ◽  
Hypoxia Inducible Factor ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
Ags Cells ◽  
Vegf Pathway ◽  
Vegfr2 Signaling

Targeting angiogenesis is an attractive strategy for the treatment of angiogenesis-related diseases, including cancer. We previously identified 23-demethyl 8,13-deoxynargenicin (compound 9) as a novel nargenicin A1 analog with potential anticancer activity. In this study, we investigated the antiangiogenic activity and mode of action of compound 9. This compound was found to effectively inhibit in vitro angiogenic characteristics, including the proliferation, invasion, capillary tube formation, and adhesion of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF). Furthermore, compound 9 suppressed the neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably, the antiangiogenic properties of compound 9 were related to the downregulation of VEGF/VEGFR2-mediated downstream signaling pathways, as well as matrix metalloproteinase (MMP)-2 and MMP-9 expression in HUVECs. In addition, compound 9 was found to decrease the in vitro AGS gastric cancer cell-induced angiogenesis of HUVECs by blocking hypoxia-inducible factor-1α (HIF-1α) and VEGF expression in AGS cells. Collectively, our findings demonstrate for the first time that compound 9 is a promising antiangiogenic agent targeting both VEGF/VEGFR2 signaling in ECs and HIF-1α/VEGF pathway in tumor cells.

scholarly journals Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5393-5399 ◽  
Author(s):  
Ronen Ben-Ami ◽  
Russell E. Lewis ◽  
Konstantinos Leventakos ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Capillary Tube ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Dependent Manner ◽  
Antiangiogenic Effect ◽  
Umbilical Vein Endothelial Cells

AbstractIn susceptible hosts, angioinvasion by Aspergillus fumigatus triggers thrombosis, hypoxia, and proinflammatory cytokine release, all of which are stimuli for angiogenesis. We sought to determine whether A fumigatus directly modulates angiogenesis. A fumigatus culture filtrates profoundly inhibited the differentiation, migration, and capillary tube formation of human umbilical vein endothelial cells in vitro. To measure angiogenesis at the site of infection, we devised an in vivo Matrigel assay in cyclophosphamide-treated BALB/c mice with cutaneous invasive aspergillosis. Angiogenesis was significantly suppressed in Matrigel plugs implanted in A fumigatus–infected mice compared with plugs from uninfected control mice. The antiangiogenic effect of A fumigatus was completely abolished by deletion of the global regulator of secondary metabolism, laeA, and to a lesser extent by deletion of gliP, which controls gliotoxin production. Moreover, pure gliotoxin potently inhibited angiogenesis in vitro in a dose-dependent manner. Finally, overexpression of multiple angiogenesis mediator–encoding genes was observed in the lungs of cortisone-treated mice during early invasive aspergillosis, whereas gene expression returned rapidly to baseline levels in cyclophosphamide/cortisone-treated mice. Taken together, these results indicate that suppression of angiogenesis by A fumigatus both in vitro and in a neutropenic mouse model is mediated through secondary metabolite production.

scholarly journals Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy

2019 ◽  
Vol 243 (2) ◽  
pp. 137-148 ◽  
Author(s):  
Wenqi Chen ◽  
Siyu Lu ◽  
Chengshun Yang ◽  
Na Li ◽  
Xuemei Chen ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Mouse Model ◽  
Serum Insulin ◽  
Tube Formation ◽  
Aberrant Expression ◽  
Angiogenesis Factors ◽  
High Insulin ◽  
Pregnant Mice

Previous research on the role of insulin has focused on metabolism. This study investigated the effect of insulin on angiogenesis in endometrial decidualization. High insulin-treated mouse model was constructed by subcutaneous injection of insulin. Venous blood glucose, serum insulin, P4, E2, FSH and LH levels in the pregnant mice were detected by ELISA. Decidual markers, angiogenesis factors and decidual vascular network were detected during decidualization in the pregnant mouse model and an artificially induced decidualization mouse model. Tube formation ability and angiogenesis factors expression were also detected in high insulin-treated HUVECS cells. To confirm whether autophagy participates in hyperinsulinemia-impaired decidual angiogenesis, autophagy was detected in vivo and in vitro. During decidualization, in the condition of high insulin, serum insulin and blood glucose were significantly higher, while ovarian steroid hormones were also disordered (P < 0.05), decidual markers BMP2 and PRL were significantly lower (P < 0.05). Uterine CD34 staining showed that the size of the vascular sinus was significantly smaller than that in control. Endometrial VEGFA was significantly decreased after treatment with high insulin in vivo and in vitro (P < 0.05), whereas ANG-1 and TIE2 expression was significantly increased (P < 0.05). In addition, aberrant expression of autophagy markers revealed that autophagy participates in endometrial angiogenesis during decidualization (P < 0.05). After treatment with the autophagy inhibitor 3-MA in HUVEC, the originally damaged cell tube formation ability and VEGFA expression were repaired. This study suggests that endometrial angiogenesis during decidualization was impaired by hyperinsulinemia in early pregnant mice.

scholarly journals In vitro antiproliferative and antiangiogenic effects of Flavin7®

2008 ◽  
pp. 413-420
Author(s):  
J Mojžiš ◽  
M Šarišský ◽  
M Pilátová ◽  
V Voharová ◽  
L Varinská ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Capillary Tube ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Nutritional Supplement ◽  
Tube Formation ◽  
Jurkat Cells ◽  
Endothelial Cell Migration

Flavin7 (F7) is a nutritional supplement often taken by cancer patients in Central Europe during chemo- and radiation therapy. In this study, investigation of the antiproliferative and antiangiogenic activities of this supplement were performed. Flavin7 showed antiproliferative activity in Jurkat as well as in HeLa cells. It significantly reduced the growth of both cancer cell lines at the doses of 200 μg/ml to 20 μg/ml (p<0.001 and p<0.01, respectively). In F7-treated Jurkat cells we found a significant increase in the fraction of cells with sub-G0/G1 DNA content, which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V staining and DNA fragmentation. Furthermore, F7 at the doses of 100 μg/ml to 4 μg/ml inhibited endothelial cell migration and capillary tube formation what indicates its potential antiangiogenic properties. Flavin7 also inhibited the activity of matrix metalloproteinases (MMPs), preferentially MMP-9, at the doses of 100 μg/ml to 4 μg/ml. Our data suggest that F7 possesses marked antiproliferative and antiangiogenic properties in vitro. Further research is needed to elucidate also its in vivo activities.

scholarly journals MiR-423-5p activated by E2F1 promotes neovascularization in diabetic retinopathy by targeting HIPK2

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Qing Xiao ◽  
Yinu Zhao ◽  
Hongjing Sun ◽  
Jia Xu ◽  
Wenjie Li ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Cell Viability ◽  
Molecular Mechanisms ◽  
Diabetic Complication ◽  
Tube Formation ◽  
Luciferase Assay ◽  
Vegf Signaling ◽  
Signaling Strategies

Abstract Background Diabetic retinopathy (DR) is a diabetic complication and the primary cause of blindness in the world. However, the treatments of DR are challenging given its complicated pathogenesis. Here, we investigated the molecular mechanisms of DR by focusing on the function of E2F1/miR-423-5p/HIPK2/HIF1α/VEGF axis. Methods Cultured retinal endothelial cells (hRMECs, hRECs) were treated with 25 mM glucose to mimic the high glucose-induced DR in vitro. Streptozotocin (STZ) was injected into mice to induce DR in mice. qRT-PCR, western blotting, immunohistochemistry, and ELISA were employed to measure levels of E2F1, miR-423-5p, HIPK2, HIF1α, and VEGF. H&E staining was utilized to examine retinal neovascularization. CCK-8 assay, transwell assay, and vascular tube formation assay were used to assess the cell viability, migration, and angiogenesis. Dual luciferase assay was performed to validate interactions between E2F1 and miR-423-5p, miR-423-5p and HIPK2. Results HG treatment increased the cell viability, migration, and angiogenesis accompanied by upregulation of E2F1, miR-423-5p, HIF1α, and VEGF levels, but reduction in HIPK2 expression. Knockdown of E2F1 or miR-423-5p suppressed the HG-induced increases in cell viability, migration, and angiogenesis. E2F1 transcriptionally activated miR-423-5p expression and miR-423-5p mimics blocked the effects of E2F1 knockdown on angiogenesis. Moreover, miR-423-5p directly targeted HIPK2 to disinhibit HIF1α/VEGF signaling. Knockdown of HIPK2 reversed the effects of miR-423-5p inhibitor on cell viability, migration, and angiogenesis. Knockdown of E2F1 suppressed neovascularization during DR in vivo. Conclusions E2F1 activates miR-423-5p transcription during DR to promote angiogenesis via suppressing HIPK2 expression to disinhibit HIF1α/VEGF signaling. Strategies targeting E2F1/miR-423-5p/HIPK2 axis could be potentially used for DR treatment.

scholarly journals Applications of Engineering Techniques in Microvasculature Design

2021 ◽  
Vol 8 ◽  
Author(s):  
Aleen Al Halawani ◽  
Ziyu Wang ◽  
Linyang Liu ◽  
Miao Zhang ◽  
Anthony S. Weiss
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Capillary Tube ◽  
Tube Formation ◽  
Engineered Tissue ◽  
Post Implantation

Achieving successful microcirculation in tissue engineered constructs in vitro and in vivo remains a challenge. Engineered tissue must be vascularized in vitro for successful inosculation post-implantation to allow instantaneous perfusion. To achieve this, most engineering techniques rely on engineering channels or pores for guiding angiogenesis and capillary tube formation. However, the chosen materials should also exhibit properties resembling the native extracellular matrix (ECM) in providing mechanical and molecular cues for endothelial cells. This review addresses techniques that can be used in conjunction with matrix-mimicking materials to further advance microvasculature design. These include electrospinning, micropatterning and bioprinting. Other techniques implemented for vascularizing organoids are also considered for their potential to expand on these approaches.

scholarly journals Anti-inflammatory Effects of Distylium racemosum Extract in a Mouse Model of Allergic Asthma

2018 ◽  
Vol 5 (02) ◽  
pp. e48-e54
Author(s):  
Jong-Heon Han ◽  
Kyuhee Park ◽  
Jong Lee ◽  
Yeon-Ju Nam ◽  
Jungeun Yang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Allergic Asthma ◽  
Cultured Cells ◽  
Inflammatory Responses ◽  
Immunoglobulin E ◽  
Phosphodiesterase 4 ◽  
Drug Classes ◽  
Anti Inflammatory

AbstractAllergic asthma is a complex disorder characterized by chronic airway inflammation. Patients with asthma often show poor adherence to corticosteroid therapy owing to prominent side effects, which provides a rationale to explore new drug classes with a better safety profile. In this study, we sought to discover natural products that inhibit the activity of phosphodiesterase 4, which is considered a potential molecular target for anti-inflammatory therapy. The screening of a plant extract library led to the identification of Distylium racemosum, which inhibited phosphodiesterase 4 activity in vitro and suppressed lipopolysaccharide-induced inflammatory signaling in cultured cells. In a mouse model of ovalbumin-induced allergic asthma, D. racemosum treatment significantly reduced inflammatory responses in the lung, as well as serum immunoglobulin E levels. Although the active constituents of D. racemosum extract and the exact mechanism underlying the in vivo action of D. racemosum remain to be elucidated, our results provide a basis for further investigation of D. racemosum extract as a novel anti-inflammatory agent for allergic asthma.

scholarly journals Tropoelastin Promotes the Formation of Dense, Interconnected Endothelial Networks

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1318
Author(s):  
Aleen Al Halawani ◽  
Lea Abdulkhalek ◽  
Suzanne M. Mithieux ◽  
Anthony S. Weiss
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Endothelial Cells ◽  
Wound Repair ◽  
Cultured Cells ◽  
Tube Formation ◽  
Endothelial Tube Formation ◽  
Angiogenic Effect

Tropoelastin, the soluble precursor of elastin, has been used for regenerative and wound healing purposes and noted for its ability to accelerate wound repair by enhancing vascularization at the site of implantation. However, it is not clear whether these effects are directly due to the interaction of tropoelastin with endothelial cells or communicated to endothelial cells following interactions between tropoelastin and neighboring cells, such as mesenchymal stem cells (MSCs). We adapted an endothelial tube formation assay to model in vivo vascularization with the goal of exploring the stimulatory mechanism of tropoelastin. In the presence of tropoelastin, endothelial cells formed less tubes, with reduced spreading into capillary-like networks. In contrast, conditioned media from MSCs that had been cultured on tropoelastin enhanced the formation of more dense, complex, and interconnected endothelial tube networks. This pro-angiogenic effect of tropoelastin is mediated indirectly through the action of tropoelastin on co-cultured cells. We conclude that tropoelastin inhibits endothelial tube formation, and that this effect is reversed by pro-angiogenic crosstalk from tropoelastin-treated MSCs. Furthermore, we find that the known in vivo pro-angiogenic effects of tropoelastin can be modeled in vitro, highlighting the value of tropoelastin as an indirect mediator of angiogenesis.

Development and investigation of thiazolidinedione and pyrazoline compounds as antiangiogenic weapons targeting VEGFR-2

2021 ◽  
Author(s):  
Neha Upadhyay ◽  
Kalpana Tilekar ◽  
Sabreena Safuan ◽  
Alan P Kumar ◽  
Markus Schweipert ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Capillary Tube ◽  
Docking Studies ◽  
Tube Formation ◽  
Cellular Migration ◽  
Antiangiogenic Activity ◽  
Nanomolar Range

Background: Angiogenesis deregulation is often linked to cancer and is thus an essential target. Materials and methods: Twenty-nine compounds were developed as VEGFR-2 inhibitors. Compounds were evaluated to determine their antiangiogenic activity. Results: B1, PB11 and PB16 showed HUVEC's IC50 scores in the submicromolar range. B1, B2 and PB16 reduced cellular migration and capillary tube formation of HUVECs. VEGFR-2 inhibitory activity was found in the nanomolar range: 200 nM of B1, 500 nM of B2 and 600 nM of PB16. B1 and PB16 suppressed the formation of new capillaries on growing CAMs. B1 and PB16 occupied the ATP site and allosteric pocket of VEGFR-2 in docking studies. Conclusion: These compounds can target VEGFR-2 and are endowed with in vitro and in vivo antiangiogenic activity.

scholarly journals Role of Phosphorylated HDAC4 in Stroke-Induced Angiogenesis

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Juan Liu ◽  
Xiang Zhou ◽  
Qing Li ◽  
Shu-Min Zhou ◽  
Bin Hu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Histone Deacetylases ◽  
Tube Formation ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Vegf Signaling ◽  
Expression Of Genes ◽  
And Migration

Acetylation or deacetylation of chromatin proteins and transcription factors is part of a complex signaling system that is involved in the control of neurological disorders. Recent studies have demonstrated that histone deacetylases (HDACs) exert protective effects in attenuating neuronal injury after ischemic insults. Class IIa HDAC4 is highly expressed in the brain, and neuronal activity depends on the nucleocytoplasmic shuttling of HDAC4. However, little is known about HDAC4 and its roles in ischemic stroke. In this study, we report that phosphorylation of HDAC4 was remarkably upregulated after stroke and blockade of HDAC4 phosphorylation with GÖ6976 repressed stroke-induced angiogenesis. Phosphorylation of HDAC4 was also increased in endothelial cells hypoxia model and suppression of HDAC4 phosphorylation inhibited the tube formation and migration of endothelial cells in vitro. Furthermore, in addition to the inhibition of angiogenesis, blockade of HDAC4 phosphorylation suppressed the expression of genes downstream of HIF-VEGF signaling in vitro and in vivo. These data indicate that phosphorylated HDAC4 may serve as an important regulator in stroke-induced angiogenesis. The protective mechanism of phosphorylated HDAC4 is associated with HIF-VEGF signaling, implicating a novel therapeutic target in stroke.

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